phaidra.vetmeduni.ac.at o:3306 DOI 10.1182/blood.2022018494 SBNO2 is a critical mediator of STAT3-driven hematological malignancies Gain-of-function mutations in the signal transducer and activator of transcription 3 (STAT3) gene are recurrently identified in patients with large granular lymphocytic leukemia (LGLL) and in some cases of natural killer (NK)/T-cell and adult T-cell leukemia/lymphoma. To understand the consequences and molecular mechanisms contributing to disease development and oncogenic transformation, we developed murine hematopoietic stem and progenitor cell models that express mutated STAT3Y640F. These cells show accelerated proliferation and enhanced self-renewal potential. We integrated gene expression analyses and chromatin occupancy profiling of STAT3Y640F-transformed cells with data from patients with T-LGLL. This approach uncovered a conserved set of direct transcriptional targets of STAT3Y640F. Among these, strawberry notch homolog 2 (SBNO2) represents an essential transcriptional target, which was identified by a comparative genome-wide CRISPR/Cas9-based loss-of-function screen. The STAT3-SBNO2 axis is also present in NK-cell leukemia, T-cell non-Hodgkin lymphoma, and NPM-ALK-rearranged T-cell anaplastic large cell lymphoma (T-ALCL), which are driven by STAT3-hyperactivation/mutation. In patients with NPM-ALK+ T-ALCL, high SBNO2 expression correlates with shorter relapse-free and overall survival. Our findings identify SBNO2 as a potential therapeutic intervention site for STAT3-driven hematopoietic malignancies. eng Notch Homolog 2; Nf-Kappa-B; Antiinflammatory Response; Mitochondrial Stat3; Gene-Expression; Cancer; Cells; Pathogenesis; Activation; Inflammation 2024-07-30T08:24:05.409Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Brandstoetter;Tania; FN:Tania Brandstoetter X-ORCID:https://orcid.org/0000-0003-4037-5352 END:VCARD BEGIN:VCARD VERSION:3.0 N:Sexl;Veronika; FN:Veronika Sexl X-ORCID:https://orcid.org/0000-0001-9363-0412 END:VCARD BEGIN:VCARD VERSION:3.0 N:Maurer;Barbara; FN:Barbara Maurer X-ORCID:https://orcid.org/0000-0003-1343-8194 END:VCARD BEGIN:VCARD VERSION:3.0 N:Mustjoki;Satu; FN:Satu Mustjoki X-ORCID:https://orcid.org/0000-0002-0816-8241 END:VCARD BEGIN:VCARD VERSION:3.0 N:Zuber;Johannes; FN:Johannes Zuber END:VCARD BEGIN:VCARD VERSION:3.0 N:Hoermann;Gregor; FN:Gregor Hoermann END:VCARD BEGIN:VCARD VERSION:3.0 N:Grebien;Florian; FN:Florian Grebien X-ORCID:https://orcid.org/0000-0003-4289-2281 END:VCARD BEGIN:VCARD VERSION:3.0 N:Eder;Thomas; FN:Thomas Eder X-ORCID:https://orcid.org/0000-0002-0932-2052 END:VCARD BEGIN:VCARD VERSION:3.0 N:Klampfl;Thorsten; FN:Thorsten Klampfl X-ORCID:https://orcid.org/0000-0002-6666-9773 END:VCARD BEGIN:VCARD VERSION:3.0 N:Huuhtanen;Jani; FN:Jani Huuhtanen X-ORCID:https://orcid.org/0000-0003-2750-4033 END:VCARD BEGIN:VCARD VERSION:3.0 N:Schmoellerl;Johannes; FN:Johannes Schmoellerl X-ORCID:https://orcid.org/0000-0002-8461-8881 END:VCARD BEGIN:VCARD VERSION:3.0 N:Grausenburger;Reinhard; FN:Reinhard Grausenburger X-ORCID:https://orcid.org/0000-0002-5972-3372 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kollmann;Sebastian; FN:Sebastian Kollmann X-ORCID:https://orcid.org/0000-0001-7911-9896 END:VCARD BEGIN:VCARD VERSION:3.0 N:Doma;Eszter; FN:Eszter Doma END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by-nc-nd/4.0 application/pdf 3334090 https://phaidra.vetmeduni.ac.at/o:3306 https://phaidra.vetmeduni.ac.at/api/object/o:3306/thumbnail LOMv1.0 discipline